Genomics of blood pressure and hypertension: extending the mosaic theory toward stratification

Lip, S. and Padmanabhan, S. (2020) Genomics of blood pressure and hypertension: extending the mosaic theory toward stratification. Canadian Journal of Cardiology, 36(5), pp. 694-705. (doi: 10.1016/j.cjca.2020.03.001) (PMID:32389342) (PMCID:PMC7237883)

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The genetic architecture of blood pressure (BP) now includes more than 30 genes, with rare mutations resulting in inherited forms of hypertension or hypotension, and 1477 common single-nucleotide polymorphisms (SNPs). These signify the heterogeneity of the BP phenotype and support the mosaic theory of hypertension. The majority of monogenic syndromes involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, and a smaller fraction are due to rare neuroendocrine tumours of the adrenal glands and the sympathetic and parasympathetic paraganglia. Somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and adenosine triphosphatases (ATP1A1 and ATP2B3) highlight the central role of calcium signalling in autonomous aldosterone production by the adrenal gland. The per-SNP BP effect is small for SNPs according to genome-wide association studies (GWAS), and all of the GWAS-identified BP SNPs explain ∼ 27% of the 30%-50% estimated heritability of BP. Uromodulin is a novel pathway identified by GWAS, and it has now progressed to a genotype-directed clinical trial. The majority of the GWAS-identified BP SNPs show pleiotropic associations, and unravelling those signals and underpinning biological pathways offers potential opportunities for drug repurposing. The GWAS signals are predominantly from Europe-centric studies with other ancestries underrepresented, however, limiting the generalisability of the findings. In this review, we leverage the burgeoning list of polygenic and monogenic variants associated with BP regulation along with phenome-wide studies in the context of the mosaic theory of hypertension, and we explore potential translational aspects that underlie different hypertension subtypes.

Item Type:Articles
Additional Information:Funding Sources: S.P. is also funded by the Medical Research Council (MR/M016560/1).
Glasgow Author(s) Enlighten ID:Lip, Dr Stefanie and Padmanabhan, Professor Sandosh
Authors: Lip, S., and Padmanabhan, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Canadian Journal of Cardiology
ISSN (Online):1916-7075
Published Online:05 March 2020
Copyright Holders:Copyright © 2020 Canadian Cardiovascular Society
First Published:First published in Canadian Journal of Cardiology 36(5):694-705
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
167816Genetic, molecular and functional dissection of a novel pathway for hypertension: Uromodulin, renal function, sodium homeostasis and blood pressure.Sandosh PadmanabhanBritish Heart Foundation (BHF)PG/12/85/29925Institute of Cardiovascular & Medical Sciences
173522Clinical study of UMOD NKCC2 interaction on salt-sensitivity in hypertensionSandosh PadmanabhanBritish Heart Foundation (BHF)CS/16/1/31878Institute of Cardiovascular & Medical Sciences
303944BHF Centre of ExcellenceRhian TouyzBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science